White matter protection by inhibitors of glial scar formation in perinatal hypoxia ischemia

围产期缺氧缺血时胶质疤痕形成抑制剂对白质的保护作用

• 批准号: 10404658
• 负责人: Stephen Arthur Back
• 金额: $ 36.19万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404658
• 关键词: Adult; Animal Model; Astrocytes; Attention; Attenuated; Blocking Antibodies; Brain; Brain Hypoxia-Ischemia; Cerebral Palsy; Cerebrum; Childhood; Chronic; Cicatrix; Clinical Trials; Cognitive; Diagnosis; Diffuse; Disease; Enzymes; Event; Extracellular Matrix; Failure; Future; Generations; Genes; Human; Hyaluronic Acid; Hyaluronidase; Hypoxia; In Vitro; Learning; Lesion; Life; Mediating; Memory; Modeling; Molecular; Motor; Natural regeneration; Neonatal; Pathway interactions; Perinatal Hypoxia; Phase; Premature Birth; Protein Subunits; Proteins; Reaction; Risk; Rodent; Role; Signal Transduction; Socialization; Survivors; TNF gene; Testing; Therapeutic; Time; Vertebral column; astrocyte progenitor; astrogliosis; central nervous system injury; connectome; disability; in vivo; inhibiting antibody; inhibitor; insight; inter-alpha-inhibitor; kinase inhibitor; myelination; nervous system disorder; neurobehavioral; neuropsychiatric disorder; novel; novel strategies; novel therapeutic intervention; novel therapeutics; oligodendrocyte progenitor; preterm newborn; prevent; progenitor; protein complex; repaired; response; src-Family Kinases; white matter; white matter injury

Project Summary Survivors of preterm birth are commonly diagnosed with persistent white matter injury (WMI) that leads to a failure of normal myelination. Myelination failure results in life long motor and neurobehavioral disabilities. The central feature of WMI is the so-called “glial scar,” an inhibitory barrier generated by reactive astrocytes, which causes myelination failure by blocking the maturation of oligodendrocyte progenitors. It is our long-term objective to develop novel therapies to prevent myelination failure by preventing glial scar formation. There are no therapeutic strategies to prevent early formation of diffuse reactive astrogliosis before it chronically blocks myelination. WMI disrupts the integrity of the hyaluronic acid (HA) backbone of the extracellular matrix. We have defined a novel pathway through which small ~5 kDa HA oligomers (HA5) regulate the proliferation of astroglial progenitors and promote reactive astrogliosis. Through the enzyme tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6), HA5 serves as a sink that traps heavy chain (HC) protein subunits of the inter-alpha-inhibitor protein (II) complex. This reaction generates unstable intermediates of II that release HC. We have identified novel approaches to block this TSG-6-dependent pathway to markedly attenuate the formation of the glial scar. Our over-riding hypothesis is that HA5-mediated HC release promotes reactive astrogliosis via a src family kinase-dependent pathway. We propose three specific aims to test this hypothesis. In aim 1, we hypothesize that hyaluronidase activation in the glial scar promotes the formation of HA5. We will determine the hyaluronidases (HYAL) that generate HA5 to promote formation of the glial scar and determine if a broad spectrum HYAL inhibitor reduces astrogliosis in response to WMI. In aim 2, we will test the hypothesis that HA5 promotes astrocyte proliferation and reactive astrogliosis through TSG-6-dependent release of heavy chains derived from II. We will determine if astrocyte proliferation in WMI is dependent on TSG-6 expression that promotes astrogliosis in vitro and in vivo via an HC-dependent mechanism. In aim 3, we hypothesize that activation of TSG-6 mediates glial scar formation via activation of src family kinases. We will first determine if a TSG-6 blocking antibody inhibits proliferation of astrocyte progenitors in vivo. We will test a src kinase inhibitor, currently in clinical trials, as a novel strategy to block glial scar formation and promote myelination. At the conclusion of these studies, we expect to define new therapeutic strategies to intervene during early WMI to prevent formation of the glial scar and promote myelination. Given that reactive astrogliosis is a central feature of many forms of CNS injury, our findings may have potential benefit for other pediatric and adult neurological disorders with prominent WMI.

项目摘要 早产的幸存者通常被诊断为持续性白色物质损伤（EEG）， 正常髓鞘形成的失败。髓鞘形成失败导致终身运动和神经行为残疾。的 胶质瘤的中心特征是所谓的“胶质瘢痕”，这是一种由反应性星形胶质细胞产生的抑制性屏障， 通过阻断少突胶质祖细胞的成熟而导致髓鞘形成失败。这是我们的长期 目的通过预防胶质瘢痕的形成，开发新的治疗方法以预防髓鞘形成障碍。 在弥漫性反应性星形胶质细胞增生症发生之前，没有预防其早期形成的治疗策略。 会长期阻碍髓鞘形成 纤维蛋白酶破坏细胞外基质的透明质酸（HA）骨架的完整性。我们定义了一个 小的~5 kDa HA寡聚体（HA 5）调节星形胶质细胞增殖的新途径 祖细胞和促进反应性星形胶质细胞增生。通过酶肿瘤 坏死 因素- （肿瘤坏死因子） 刺激 基因-6（TSG-6），HA 5作为一个接收器，捕获α间抑制剂的重链（HC）蛋白亚基 蛋白质（I）复合物。该反应产生释放HC的不稳定中间体I？I。我们有 确定了阻断这种TSG-6依赖性途径的新方法，以显著减弱 胶质瘢痕我们的主要假设是HA 5介导的HC释放促进反应性星形胶质细胞增生 通过SRC家族激酶依赖性途径。我们提出了三个具体目标来检验这一假设。在aim中 1，我们假设胶质瘢痕中透明质酸酶的激活促进了HA 5的形成。我们将 确定产生HA 5以促进神经胶质瘢痕形成的透明质酸酶（HYAL），并确定 一种广谱HYAL抑制剂减少了对HLA-A反应的星形胶质细胞增生。在目标2中，我们将测试 HA 5通过TSG-6依赖性促进星形胶质细胞增殖和反应性星形胶质细胞增生的假说 释放源自I型胶原的重链。我们将确定星形胶质细胞的增殖是否依赖于 TSG-6表达通过HC依赖性机制在体外和体内促进星形胶质细胞增生。在目标3中， 我们假设TSG-6的激活通过src家族激酶的激活介导神经胶质瘢痕形成。我们 将首先确定TSG-6阻断抗体是否在体内抑制星形胶质细胞祖细胞的增殖。我们将 测试src激酶抑制剂，目前在临床试验中，作为一种新的策略，以阻止神经胶质瘢痕的形成， 促进髓鞘形成。在这些研究的结论中，我们希望确定新的治疗策略， 早期干预以防止胶质瘢痕的形成并促进髓鞘形成。鉴于反应性 星形胶质细胞增生是许多形式的中枢神经系统损伤的中心特征，我们的发现可能对其他神经系统损伤有潜在的益处。 小儿和成人神经系统疾病，具有突出的神经功能障碍。